Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide

ABSTRACT

Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide having advantageous properties for formulation as an analgesic or antiinflammatory agent.

BACKGROUND OF THE INVENTION

The present invention is directed to a novel crystalline anhydroussodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide havingadvantageous properties for pharmaceutical formulation as an analgesicor antiinflammatory agent.

Kadin, U.S. Pat. No. 4,556,672 has disclosed said5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide, of the formula ##STR1##(or a pharmaceutically acceptable salt) as an especially preferredcompound for use as an analgesic or antiinflammatory agent. In thatdisclosure the sodium salt of the compound of the formula (I) wasalternatively isolated as a hemihydrate or hydrate. The monohydrate wasrendered anhydrous by further drying. We have now determined thatseveral hydrates are formed, generally as mixtures having variousmorphologies (e.g., amorphous and needle shaped crystals). These varioushydrated forms generally have flow and electrostatic properties whichmake formulation difficult. We have also determined that the anhydrousproduct obtained by simple drying at elevated temperature and/or reducedpressure is amorphous and hygroscopic. It was therefore highly desirableto find a crystalline form of the sodium salt which might overcome thesedifficulties.

SUMMARY OF THE INVENTION

We have now found an anhydrous, crystalline form of the sodium salt of5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide which possesses valuableand unobvious properties. Thus, this salt is readily handled andformulated into dosage forms such as capsules. It is not hygroscopic,remaining stable in dosage forms even at 90% relative humidity. Whencompacted into tablets, it dissolves more rapidly than the hydratedsalt.

This advantageous crystalline salt is generally formulated and used asan analgesic according to earlier disclosure of Kadin, cited above,hereby incorporated by reference.

Surprisingly, it is simply prepared by stirring a hydrated form of thesodium salt in acetonitrile at ambient temperature. This transformationhas been observed in no other solvent at that temperature, although itdoes occur less conveniently in refluxing toluene.

DETAILED DESCRIPTION OF THE INVENTION

Once discovered, the present invention is readily carried out. In thisprocess the sodium salt of the compound of the formula (I) is preferablyfirst isolated in the form of its hydrate, which is then simply stirredin acetonitrile to obtain the present advantageous, anhydrous,non-hygroscopic, crystalline sodium salt. The temperature of thistransformation in acetonitrile is not critical, but it is convenientlycarried out at ambient temperature, avoiding the energy costs of eitherheating or cooling. The transformation is alternatively, but much lessconveniently carried out in toluene with azeotropic removal of water bymeans of a Dean-Stark trap at the reflux temperature of toluene. Sincelower boiling benzene is much less efficient in this process, generallyproducing anhydrous product which is amorphous, it is believed that useof higher temperatures are critical to the anhydrous crystal formationwhen the solvent is other than acetonitrile.

The present crystalline salt is characterized by its particular physicalproperties as noted below. It is generally formulated and used asearlier disclosed by Kadin, cited above. A particular, stable andclinically useful capsule formulation comprising the present salt isexemplified below.

The following examples are given by way of illustration and are not tobe construed as limitation of this invention, many variations of whichare possible within the scope and spirit thereof.

PREPARATION 1 Hydrated Sodium Salt of5-Chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide

Title hydrates are prepared according to Example 10 of Kadin, U.S. Pat.No. 4,556,672. Alternatively,5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide (Example 8 of saidKadin; 51.2 g., 0.16 mol) was suspended in 400 ml. CH₃ CN at 40° C.Concurrently, NaHCO₃ (14.1 g., 0.168 mol) was dissolved in 200 ml. of H₂O and warmed to 40° C. The warm aqueous solution was added to the warmacetonitrile suspension over 20 minutes, during which slight foaming wasnoted. The resulting solution was stirred at 40° C., treated with 5 g.of decolorizing carbon, stirred at 25° C. for 30 minutes and filteredwith 50 ml. of 1:1 CH₃ CN:H₂ O for wash. The combined filtrate and washwas concentrated in vacuo over a steam bath as the acetonitrile wasdisplaced with 200 ml. of water to a final volume of about 500 ml.,cooled to 25° C. and a first crop recovered by filtration. The solidswere washed with 50 ml. of water. The combined mother liquor and washwas stripped to 400 ml. to yield a second crop. After drying under air,the first crop weighed 35.76 g. (6.4% water) and the second crop weighed16.77 g. (6.2% water), a 90% yield corrected for H₂ O content. The waterlevel calculated for the monohydrate is 5.0%. Differential scanningcalorimetry on these two crops showed 4 endotherms (at about 110, 150,237 and 255).

EXAMPLE 1 Anhydrous, Crystalline Sodium Salt of5-Chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide

Hydrated sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide(52.5 g., prepared according to the alternative method of Preparation 1)was stirred at ambient temperature in 52.5 ml. of CH₃ CN. Title productwas recovered by filtration, with 50 ml. CH₃ CN wash, and dried at 55°C. in vacuo to yield 46.7 g.(95%) of title product; crystalline underthe polarizing microscope; differential scanning calorimetry over therange 50°-300° C. shows a single sharp endotherm at 255°±2° C. Anal.Calcd. for C₁₄ H₈ ClN₂ O₃ Sna: C, 49.06; H, 2.35; N, 8.18; S, 9.35; Cl,10.34; Sulfated Ash, 20.72; H₂ O, O; Less on drying in vacuum at 100°C., O. Found: C, 48.85; H, 2.39; N, 8.22; S, 9.54; Cl, 10.43; SulfatedAsh, 20.58; H₂ O, 0.07; Loss on drying in vacuum at 100° C., 0.07.

In marked contrast to the hydrated form, which is orange in color, thepresent anhydrous sodium salt is yellow.

Samples of the hydrated form (Preparation 1) and the present anhydrousform were reduced to a fine particle size and compacted into tablets ina 1/2 inch diameter die at a final pressure of 2000 lb. In each case,the punch was removed and that end of the die covered by parafilm inorder to permit testing of dissolution rate from a single flat surfaceof known surface area. The die containing the compressed drug was placedin the bottom of a USP dissolution flask with paddle 2.5 cm. above theexposed drug surface. At 25° C., both in H₂ O and in 0.05M borate bufferat pH 9.0, the intrinsic dissolution rate (which can be an importantfactor in the efficacy of oral dosage forms) was approximately threetimes faster for the anhydrous form than for the hydrate.

The anhydrous form shows little tendency to reform the hydrate. Even ina water wet granulation employed below in the preferred preparation ofcapsules, the hydrate was not formed (as evidenced by a lack of colorchange from yellow towards orange).

EXAMPLE 2 Oral Capsule Dosage Form Containing the Anhydrous Sodium of5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide

The following ingredients were blended, wet granulated with 875 ml. ofwater and finally dried to 5% water by Karl Fischer:

    ______________________________________                                        Sodium salt of 5-chloro-3-                                                                          600.00 g.                                               (2-thenoyl)-2-oxindole-1-                                                                           (561.52 g.A*)                                           carboxamide                                                                   Microcrystalline cellulose                                                                          885.75 g.                                               (Avicel PH101)                                                                Hydrated corn starch  236.25 g.                                               Povidone (PVC-30)     105.00 g.                                               ______________________________________                                         (*A refers to the activity equivalent as free acid)                      

The dried, wet granulated powder was then further blended with:

    ______________________________________                                        Sodium starch glycolate                                                                         210.00 g.                                                   (Explotab)                                                                    Magnesium stearate                                                                              42.00 g.                                                    Sodium lauryl sulfate                                                                           21.00 g.                                                    ______________________________________                                    

Soft gelatin capsules containing 100 mg.A were prepared on aconventional capsule filling machine, using a fill weight of 375 mg. ofthe finished blend. These capsules demonstrated excellentbioavailability when orally dosed in dogs, showing by blood levels ahigh 89% bioavailability relative to an orally dosed solution.

We claim:
 1. Anhydrous, crystalline sodium salt of5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide.
 2. A pharmaceuticalcomposition for oral use in man comprising an analgesic orantiinflammatory effective amount of the salt of claim 1 and apharmaceutically acceptable carrier or diluent.
 3. A method of orallytreating pain or inflammatory conditions in man which comprisesadministering an analgesic or antiinflammatory effective amount of thesalt of claim 1.